One-pot synthesis of α-alkylated nitriles with carbonyl compounds through consecutive aldol reaction/hydrogenation using a hydrotalcite-supported palladium nanoparticle as a multifunctional heterogeneous catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.06.053

α-Alkylation of various nitriles with carbonyl compounds successfully proceeded using a hydrotalcite-supported palladium nanoparticle as a multifunctional catalyst. The alkylated nitriles were formed through aldol reaction at base sites on the hydrotalcite surface followed by hydrogenation by molecular hydrogen on the palladium nanoparticle.

Full text of DOI:10.1016/j.tetlet.2005.06.053

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5507–5510
One-pot synthesis of a-alkylated nitriles with carbonyl
compounds through consecutive aldol reaction/hydrogenation
using a hydrotalcite-supported palladium nanoparticle as
a multifunctional heterogeneous catalyst
Ken Motokura, Noriaki Fujita, Kohsuke Mori, Tomoo Mizugaki,
Kohki Ebitani and Kiyotomi Kaneda*
Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama,
Toyonaka, Osaka 560-8531, Japan
Received 23 May 2005; revised 6 June 2005; accepted 10 June 2005
Available online 1 July 2005
Abstract—a-Alkylation of various nitriles with carbonyl compounds successfully proceeded using a hydrotalcite-supported palla-
dium nanoparticle as a multifunctional catalyst. The alkylated nitriles were formed through aldol reaction at base sites on the hydro-
talcite surface followed by hydrogenation by molecular hydrogen on the palladium nanoparticle.
Ó 2005 Elsevier Ltd. All rights reserved.
Multifunctional catalysts provide a green and efficient
method for the one-pot synthesis of valuable organic
compounds in both laboratory and industrial chemis-
try.1,2 Of the various types of multifunctional catalyst,
solid catalysts with different types of active sites on the
surface have attracted considerable interest; their advan-
tages include a simple work-up procedure, the ability to
recycle the catalyst, and the easy creation of catalytically
active centers on solid surface.3 Hydrotalcites (HTs),
having cation and anion exchange abilities, strong sur-
face basicity, and adsorption ability, are excellent inor-
ganic materials for the evolution of high-performance
heterogeneous catalysts.4–6 We have recently reported
the potential use of the HTs as multifunctional catalysts,
and reported a ruthenium-grafted hydrotalcite catalyst
(Ru/HT) for the one-pot synthesis of a-alkylated nitr-
iles3c and quinoline derivatives.3d
From the standpoint of environmental friendliness, the
catalytic synthesis of a-alkylated nitriles, which are
3
R
3
R
Table 1. Aldol reaction of 1 with 2 using various solid base catalystsa
1
1
R
2
+
+
+
+
base-HX
base
CN
CN
R
R
R
2
R
X
catalyst
CN
CO Et
2
+
Ph
NC CO Et
2
Ph
O
CN
ð1Þ
ð2Þ
1
2
3
Entry
Catalyst
Yield of 3 (%)b
3
R
3
R
1
2
3
4
5
6
Pd/HT
HT
Al2O3
99
99
52
3
1
Pd/HT, H
2
1
R
H O
2
2
+
R
2
R
O
CN
MgO
Al(OH)3
Mg(OH)2
2
2
Keywords: a-Alkylation of nitrile; Aldol reaction; Hydrogenation;
One-pot synthesis; Palladium; Hydrotalcite; Heterogeneous catalyst.
a 1 (1.0mmol), 2 (1.0 mmol), catalyst (0.025 g), toluene (3 mL), 80 °C,
1 h.
b Determined by GC.
*
Corresponding author. Tel./fax: +81 6 68506260; e-mail: kaneda@
cheng.es.osaka-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.053

5508
K. Motokura et al. / Tetrahedron Letters 46 (2005) 5507–5510
important building blocks of various biologically active
Pd-catalyst (1mol%)
(1 atm),
CO Et
CO Et
2
2
Ph
Ph
compounds7 is attractive: traditional synthetic routes
require the use of alkyl halides and strong homogeneous
bases in stoichiometric quantities (Eq. 1). We have al-
ready demonstrated the effectiveness of the Ru/HT cat-
alyst for direct a-alkylation of nitriles with primary
alcohols3c,8 however, this catalyst system needs a high
reaction temperature and is only effective using aryl-
acetonitriles as substrates.9 In this paper, we report a
hydrotalcite-supported palladium nanoparticle catalyst
(Pd/HT) for the one-pot a-alkylation of diverse sets of
H
2
CN
CN
4
o
toluene, 60 C, 1 h
3
yield of 4 (%)
Pd/HT
Pd/Carbon (0.5 wt%)
Pd/Carbon (5.0 wt%)
98
94
49
Scheme 1.
Table 2. a-Alkylation of various nitriles with carbonyl compounds using the Pd/HTa
3
3
R
3
R
R
1
1
Pd/HT, H
Pd/HT
1
2
R
R
2
+
2
NC
R
R
2
R
O
R
(i)
(ii)
CN
CN
Entry
1
Nitrile
Acceptor
Time of (ii) (h)
1
Product
Yields (%)b
98
CO Et
2
O
NC CO Et
2
CN
1
2
2
CN
CN
CONH
2
5
4
1
82
NC CN
2
3c,d
NC CONH
2
2
95e
99
2
CN
SO Ph
2
4
NC SO Ph
2
CN
N
NC
N
5
2
2.5
23
99
84
CN
O
6f
NC
O N
2
CN
CO Et
H N
2
O
2
7c
1
4
1
87
Cl
CN
CO Et
2
O
O
8
1
99
CN
CO Et
2
9
1
2
98
CN
CO Et
S
2
S
10
11
12c,g
13
14
1
24
3
19
O
O
CN
CO Et
O
O
2
1
82
CN
CO Et
2
1
HCHO
1
91
CN
CO Et
2
1
1
85(81)
97(92)
O
CN
CN
CN
6.5
NC CN
O
a (i): Nitrile (1 mmol), carbonyl compounds (1 mmol), Pd/HT (0.1 g; Pd: 0.01 mmol), toluene (3 mL), 2 h, 80 °C, Ar. (ii): 60 °C, H2 (1 atm).
b Determined by GC using an internal standard. Values in parentheses are isolated yield.
c DMF (3 mL) was used as solvent.
d (i): 18 h.
e Determined by 1H NMR analysis.
f (i): 120 °C.
g 30% aqueous HCHO was used, (i): 3 h.

K. Motokura et al. / Tetrahedron Letters 46 (2005) 5507–5510
5509
nitriles with carbonyl compounds via aldol condensa-
tion and hydrogenation (Eq. 2).10,11
presence of water: a-alkylation of 1 using aqueous
30% formaldehyde afforded ethyl 2-cyanopropionate in
91% yield (entry 12). Cyclohexanone also acted as an
acceptor to yield the corresponding alkylated product
(entry 14).
The Pd/HT was prepared as follows: the HT, Mg6-
Al2(OH)16CO3,12 (1.0g) was added to 100mL of an
aqueous PdCl2 (0.1 mmol) solution containing KCl
(0.1 g). The heterogeneous mixture was stirred at 25 °C
for 1 h under air to afford a pale yellow powder, then
successively reduced in the presence of 1 atm H2 at
100 °C for 8 h. The solid product was isolated by centri-
fugation, washed thoroughly with deionized water and
dried at 110 °C for 12 h, affording the Pd/HT as a black
powder (Pd content: 1.0wt %). The prepared Pd/HT
was characterized by X-ray diffraction (XRD), energy-
dispersive X-ray spectroscopy (EDX), and transmission
electron microscopy (TEM). XRD peak positions of the
Pd/HT were identical to those of the parent HT. The ab-
sence of chlorine and potassium was confirmed by EDX
analysis. TEM analysis revealed highly dispersed Pd
This Pd/HT catalyst was easily separated from the reac-
tion mixture by a simple filtration. The recovered cata-
lyst was washed with toluene, which could be reused
with retention of its high catalytic activity and selectiv-
ity: the three recycling reactions of 1 with 2 had yields
over 90%. Inductively coupled plasma analysis of the fil-
trate showed no leaching of the Pd species during the
above reactions (detection limit 0.03 ppm).
In conclusion, we have demonstrated a multifunctional
catalysis of the Pd/HT for the one-pot synthesis of a-
alkylated nitriles from the reaction of various nitriles
with various carbonyl compounds. This reaction sys-
tem has advantages such as (i) high catalytic activity
and selectivity, (ii) applicability toward diverse sets of
substrates, (iii) the only byproduct is water, and (iv)
simple work-up and ability to reuse of the catalyst.
Heterogeneous catalysts that possess a multifunctional
surface will act as pivotal tools in the development of
economically and environmentally friendly chemical
processes.
˚
nanoclusters with a mean diameter of ca. 70A (standard
˚
deviation 14 A) on the Pd/HT surface.
The catalytic activity of the Pd/HT for aldol reaction of
ethyl cyanoacetate (1) with benzaldehyde (2) was com-
pared with those of various solid base catalysts (Table
1). The Pd/HT as well as its precursor HT showed a high
performance for the aldol reaction affording (E)-ethyl 2-
cyano-3-phenyl-2-propenoate (3) (entries 1 and 2).
Other heterogeneous bases, such as Al2O3, MgO,
Al(OH)3, and Mg(OH)2 were less active under the pres-
ent reaction conditions (entries 3–6). After the aldol
condensation using the Pd/HT, treatment with an atmo-
spheric H2 at 60 °C gave ethyl 2-cyano-3-phenylpropano-
ate (4) in an excellent yield. Interestingly, the catalytic
activity of the Pd/HT for the hydrogenation of 3 is supe-
rior to those of commercially available Pd/carbons13
(Scheme 1).
Acknowledgments
This work was supported by a Grant-in-Aid for Scien-
tific Research from JSPS and the center of excellence
(21COE) program ÔCreation of Integrated EcoChem-
istryÕ of Osaka University. TEM measurements were
conducted at the Research Center for Ultrahigh Voltage
Electron Microscopy at Osaka University. We are also
grateful to the Department of Materials Engineering
Science, Graduate School of Engineering Science, Osaka
University, for scientific support with the gas-hydrate
analyzing system (GHAS) and lend-lease laboratory
system.
One-pot syntheses of various a-alkylated nitriles using
carbonyl compounds were attempted in the presence
of the Pd/HT catalyst, as summarized in Table 2.14,15
A wide variety of nitriles and carbonyl compounds re-
acted to give excellent yields of a-alkylated nitriles; suc-
cessive hydrogenation of olefinic double bonds occurred
selectively leaving intact cyano, ester, amide, and sulfox-
ide groups (entries 1–4). On the other hand, several
functional groups such as, furan ring, aromatic chloro
and nitro groups, were reduced under the present alkyl-
ation reaction (entries 6, 7, and 11). a-Alkylation of mal-
ononitrile with 2 gave 2-benzylmalononitrile, a highly
useful intermediate for the synthesis of a,a-dialkylated
amino acids,7b in an 82% yield (entry 2). Furthermore,
3-phenyl-2-(2-pyridyl)propionitrile, a precursor of anti-
arrhythmic agents, was obtained by the Pd/HT catalyst
system in a quantitative yield (entry 5), while the tradi-
tional method using benzyl chloride and a stoichiome-
tric amount of NaNH2 gave 52% yield.16 In the
reaction of an a,b-unsaturated aldehyde, no 1,4-adduct
(Michael-type product) was obtained (entry 9).
Although the aldol reaction of 1 with 2-thiophenecar-
boxaldehyde proceeded smoothly, hydrogenation of
the unsaturated nitrile scarcely occurred (entry 10).
The Pd/HT catalyst showed a high activity even in the
References and notes
1. Hall, N. Science 1994, 266, 32.
2. (a) For excellent reports of one-pot reactions, see: Koeller,
K. M.; Wong, C.-H. Chem. Rev. 2000, 100, 4465; (b)
Gelman, F.; Blum, J.; Avnir, D. J. Am. Chem. Soc. 2002,
124, 14460; (c) Kawasaki, T.; Yamamoto, Y. J. Org.
´
Chem. 2002, 67, 5138; (d) Gomez, A. M.; Pedregosa, A.;
Valverde, S.; Lopez, J. C. Chem. Commun. 2002, 2022; (e)
´
Balme, G.; Bossharth, E.; Monterio, N. Eur. J. Org.
Chem. 2003, 4101.
3. (a) Choudary, B. M.; Chowdari, N. S.; Madhi, S.;
Kantam, M. L. J. Org. Chem. 2003, 68, 1736; (b) Sels,
B. F.; De Vos, D. E.; Jacobs, P. A. Angew. Chem., Int.
Ed. 2004, 44, 310; (c) Motokura, K.; Nishimura, D.;
Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am.
Chem. Soc. 2004, 126, 5662; (d) Motokura, K.; Mizugaki,
T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2004, 45,
6029.
4. For reviews of HT catalysts, see: Sels, B. F.; De Vos, D.
E.; Jacobs, P. A. Catal. Rev. 2001, 43, 443.

5510
K. Motokura et al. / Tetrahedron Letters 46 (2005) 5507–5510
5. Recent examples of transition metal-exchanged HT cata-
A: Gen. 1998, 169, 207; (b) Kakiuchi, N.; Maeda, Y.;
Nishimura, T.; Uemura, S. J. Org. Chem. 2001, 66, 6620;
(c) Choudary, B. M.; Madhi, S.; Chowdari, N. S.;
Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002,
124, 14127.
lysts: (a) Sels, B.; De Vos, D.; Buntinx, M.; Pierard, F.;
Kirsch-De Mesmaeker, A.; Jacobs, P. Nature 1999, 400,
855; (b) Matsushita, T.; Ebitani, K.; Kaneda, K. Chem.
Commun. 1999, 265; (c) Choudary, B. M.; Chowdari, N.
S.; Karangula, J.; Kantam, M. L. J. Am. Chem. Soc. 2002,
124, 5341.
11. Recently, a Rh complex anchored on a silica matrix was
reported for one-pot synthesis of ethyl 2-cyano-3-phenyl-
propanoate: Goettmann, F.; Grosso, D.; Mercier, F.;
Mathey, F.; Sanchez, C. Chem. Commun. 2004, 1240.
12. The HT, Mg6Al2(OH)16CO3, was obtained from
TOMITA Pharmaceutical Co., Ltd.
13. The Pd/carbons were purchased from N.E. Chemcat Co.
Ltd (0.5 wt %) and Wako Pure Chemical Ind., Ltd
(5.0wt %).
14. In a large-scale reaction, 1 (1.70g, 15 mmol), 2 (1.59 g,
15 mmol), the Pd/HT (0.1 wt %, 0.60 g, Pd: 0.006 mmol),
and toluene (20mL) was used. After the aldol reaction
(80 °C, 3 h) and the hydrogenation (80 °C, 20h), the
catalyst was filtered and GC analysis of the filtrate showed
a 97% yield of 4. The filtrate was evaporated and the crude
product was purified by distillation (180 °C/5.0mmHg) to
afford pure product (2.9 g, 95% yield, TON = 2380).
15. In the one step reaction (aldol reaction under H2) using 1
with 2, corresponding alkylated product (4) was obtained,
however, the yield was low (61%, after 1 h, 80 °C)
compared to that in the consecutive reaction and benzyl
alcohol was formed as a byproduct.
6. Base catalysis of HTs: (a) Kantam, M. L.; Choudary, B.
M.; Reddy, C. V.; Rao, K. K.; Figueras, F. Chem.
Commun. 1998, 1033; (b) Yamaguchi, K.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Org. Chem.
2000, 65, 6897.
7. (a) Hartmann, R. W.; Batzl, C. J. Med. Chem. 1986, 29,
1362; (b) Wu, Z.-L.; Li, Z.-Y. J. Org. Chem. 2003, 68,
2479; (c) Takaya, H.; Yoshida, K.; Isozaki, K.; Terai, H.;
Murahashi, S.-I. Angew. Chem., Int. Ed. 2003, 42, 3302.
8. For homogeneous catalytic a-alkylation of nitriles with
primary alcohols, see: (a) Grigg, R.; Mitchell, T. R. B.;
Sutthivaiyakit, S.; Tongpenyai, N. Tetrahedron Lett. 1981,
22, 4107; for a-alkylation of ketones with primary
alcohols, see also: (b) Cho, C. S.; Kim, B. T.; Kim,
T.-J.; Shim, S. C. Tetrahedron Lett. 2002, 43, 7987; (c)
Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi,
S.; Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72.
9. For example, the reaction of ethyl cyanoacetate (1) with
benzyl alcohol using the Ru/HT afforded undesirable
benzyl cyanoacetate (base-catalyzed transesterification
product) and the alkylation product was not formed.
10. For other hydrotalcite-supported palladium catalysts, see:
(a) Chen, Y. Z.; Hwang, C. M.; Liaw, C. W. Appl. Catal.
16. Bernhart, C. A.; Condamine, C.; Demarne, H.; Roncucci,
R.; Gagnol, J.-P.; Gautier, P. J.; Serre, M. A. J. Med.
Chem. 1983, 26, 451.